Microglial PHOX and Mac‐1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha‐synuclein

Abstract

alpha-Synuclein, a gene whose mutations, duplication, and triplication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant alpha-synuclein has been attributed to date largely to faster formation of alpha-synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) alpha-synuclein-elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated alpha-synuclein could activate microglia more powerfully than WT alpha-synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that alpha-synuclein with the A30P or A53T mutations caused greater microglial activation than WT alpha-synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant alpha-synuclein. Mutant alpha-synuclein also induced greater production of reactive oxygen species than WT alpha-synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen-1 (Mac-1) receptor, rather than alpha-synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant alpha-synuclein.

α-Synuclein Activates Microglia by Inducing the Expressions of Matrix Metalloproteinases and the Subsequent Activation of Protease-Activated Receptor-1

“…Of the pattern recognition receptors implicated in microglial activation, macrophage Ag complex-1 (Mac-1) and CD36 (class B scavenger receptor) have been recently reported to mediate asynuclein-induced microglial activation (20,41). Zhang et al (41) reported that a-synuclein directly binds to Mac-1 receptors, which then activate NADPH oxidase to produce ROS.…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…LPS induces a rapid activation of microglia and a delayed, progressive and selective destruction of nigral dopaminergic neurons both in vivo and in vitro ( [78,77,79]). Finally, using mice carrying a deletion in the gene coding for NADPH oxidase, one major source of intracellular ROS, or in Mac-1 it has been possible to clearly demonstrate that the production of ROS by LPSactivated microglia is directly toxic to neurons as well as the secretion of proinflammatory molecules, which foster neurodegeneration as well ( [182,190,252,265,264]). …”

Alpha-Synuclein and the Immune Response in Parkinson’s Disease

“…Moreover, following the discovery that Syn aggregates can be released from neurons and transmitted to neighbouring cells (Desplats et al, 2009), a study has recently shown that Syn release by SH-SY5Y neuroglioma cells, especially when treated with MPP + neurotoxin, are able to activate the inflammatory response in a microglial cell line (Alvarez-Erviti et al, 2011). Up to this point, research on Syn-mediated cell response has focused primarily on the effects on neuroinflammation (Benner et al, 2008) or microglial activation (Cookson, 2009;Reynolds et al, 2008a;Thomas et al, 2007;Zhang et al, 2007;Zhang et al, 2005) of Syn in its aggregated form. Interestingly, Reynolds and coworkers (Reynolds et al, 2008b) have found that nitrated, aggregated Syn (N-Syn) has a stronger stimulating effect on microglia than that of nitrated but non-aggregated Syn.…”